1,3-Dihydro-6-(pyridinyl)-2H-imidazo[4,5-b]pyridin-2-ones and -imidazo[4,5-b]pyridine-2-thiones and their cardiotonic use

ABSTRACT

1,3-Dihydro-1-R 1  -3-R 3  -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones or -2-thiones or pharmaceutically-acceptable acid-addition salts thereof, which are useful as cardiotonic agents, where Q is hydrogen or lower-alkyl, R 1  and R 3  are each hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene and NB is di-(lower-alkyl)amino or 4-morpholinyl, at least one of R 1  and R 3  being hydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two substituents, are prepared by reacting a 2-R 3  NH-3-R 1  NH-5-PY-6-Q-pyridine with urea or carbonyldiimidazole to produce said -2-one or with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole to produce said -2-thione. Also shown and claimed are cardiotonic compositions and a method for increasing cardiac contractility using said cardiotonic agents. Also shown are processes for preparing said intermediate 2-R 3  NH-3-R 1  NH-5-PY-6-Q-pyridines and other intermediates used in said processes.

CROSS-REFERENCE TO RELATED APPLICATION

The intermediate 2-R₃ NH-3-R₁ NH-5-PY-6-Q-pyridines and intermediatestherefore and preparation thereof, which are shown herein, where R₁, R₃,PY and Q are defined hereinbelow, are disclosed claimed in copendingpatent application Ser. No. 135,100, filed Mar. 28, 1980.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 2H-imidazo[4,5-b]pyridin-2-ones and-2-thiones, their preparation and their use as cardiotonics.

(b) Description of the Prior Art

Baldwin et al [J. Med. Chem. 20, 1189-1193 (1977)] prepared2-(3-pyridinyl)-1H-imidazo[4,5-b]pyridine and2-(4-pyridinyl)-1H-imidazo[4,5-b]pyridine by heating respectively, amixture of 2,3-diaminopyridine and nicotinic acid or a mixture of2,3-diaminopyridine and nicotinic acid or a mixture of2,3-diaminopyridine and isonicotinic acid. Both of these compounds werefound by Baldwin et al to be inactive when tested as inhibitors ofxanthine oxidase.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention relates to1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones and-2-thiones and pharmaceutically-acceptable acid-addition salts thereof,which are useful as cardiotonic agents, where R₁, R₃, PY and Q aredefined hereinbelow.

The invention in a process aspect comprises reacting a 2-R₃ NH-3-R₁NH-5-PY-6-Q-pyridine with urea or carbonyldiimidazole to produce1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or withan alkali metal lower-alkyl xanthate, thiourea orthiocarbonyldiimidazole to produce 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridine-2-thione.

A composition aspect of the invention relates to a cardiotoniccomposition for increasing cardiac contractility in a patient, saidcomposition comprising a pharmaceutically-acceptable carrier and, as theactive ingredient thereof, an effective amount of a cardiotonic1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or-2-thione or pharmaceutically acceptable acid-addition salt thereof.

In a method aspect, the invention relates to a method for increasingcardiac contractility in a patient requiring such treatment whichcomprises the administration of a medicament comprising apharmaceutically-acceptable carrier and, as the active component,thereof, an effective amount of the cardiotonic 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thione orpharmaceutically-acceptable acid-addition salt thereof.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

In a composition of matter aspect the invention resides in a1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or-2-thione having formula I ##STR1## where Z is O or S, Q is hydrogen orlower-alkyl R₁ and R₃ each are hydrogen, lower-alkyl,lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB whereY is lower-alkylene having at least two carbon atoms between itsconnecting linkages and NB is di-(lower-alkyl)amino or 4-morpholinyl, atleast one of R₁ or R₃ being hydrogen, and PY is 4- or 3-pyridinyl or 4-or 3-pyridinyl having one or two lower-alkyl substituents, orpharmaceutically-acceptable acid-addition salts thereof. The compoundsof formula I are useful as cardiotonic agents, as determined by standardpharmacological evaluation procedures. Preferred embodiments are thoseof formula I where PY is 4-pyridinyl or 3-pyridinyl, Z is O, R₁ ishydrogen when R₃ is methyl, ethyl or 2-hydroxyethyl, and R₃ is hydrogenwhen R₁ is methyl, ethyl or 2-hydroxyethyl, and Q is hydrogen, methyl orethyl. Particularly preferred embodiments are the compounds of formula Iwhere Z is O, R₁ is hydrogen, R₃ is 2-hydroxyethyl, PY is 4-pyridinyland Q is hydrogen, methyl or ethyl.

The compound of formula I may exist in tautomeric forms, that is, whenR₁ is hydrogen as 1,3-dihydro-3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thione of formula Iand/or 3-R₃ -6-PY-5-Q-3H-imidazo[4,5-b]pyridine-2-ol or -2-thiol offormula IA, illustrated as follows ##STR2## or when R₃ is hydrogen as1,3-dihydro-1-R₁ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thioneof formula I and/or 1-R₁ -6-PY-5-Q-1H-imidazo[4,5-b]pyridine-2-ol or-2-thiol of formula IB, illustrated as follows ##STR3## Structuralpreferences for other known imidazo[4,5-b]pyridin-2-ones or -2-thioneswould indicate the above formula I to be the preferred tautomericstructure; thus, we have preferred to use the names based on structureI, although it is understood that in either above instance where R₁ orR₃ is hydrogen that either or both structures are comprehended herein.

In a process aspect the invention resides in the process of producingthe 1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridine-2-one or-2-thione of formula I which comprises reacting 2-R₃ NH-3-R₁NH-5-PY-6-Q-pyridine (II) with urea or carbonyldiimidazole to producethe 2-one (I where Z is O) or with an alkali metal xanthate, thiourea orthiocarbonyldiimidazole to produce the 2-thione (I where Z is S), wherePY, R₁, R₃, Z and Q have the meanings given above for the compound offormula I. Preferred embodiments of this process are those which producethe above-said preferred composition embodiments of formula I. Thisprocess aspect is disclosed and claimed in copending divisionalapplication Ser. No. 236,147, filed on Feb. 20, 1981.

A composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, an effective amount of a cardiotonic 1,3-dihydro-1-R₁-3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one (I) where Z is O) or2-thione (I where Z is S) of formula I, where Z, R₁, R₃, PY and Q areeach defined as in formula I, or pharmaceutically-acceptableacid-addition salt thereof. Preferred embodiments are those having asactive components the above-said preferred embodiments of formula I.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient an effective amount of a cardiotonic1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one (I whereZ is O) or -2-thione (I where Z is S) of formula I where PY, R₁, R₃ andZ are defined as in formula I, or pharmaceutically-acceptableacid-addition salts thereof. Preferred embodiments of this method aspectare those using the preferred cardiotonics of formula I noted above.

The term "lower-alkyl" as used herein, e.g., as one of the meanings forR₁, R₃ or Q or as a substituent for PY in formula I, means alkylradicals having from 1 to 6 carbon atoms which can be arranged asstraight or branched chains, illustrated by methyl, ethyl, n-propyl,isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl,and the like.

Illustrative of PY in formula I where PY is 4-, 3- or 2-pyridinyl having1 or 2 lower-alkyl substituents are the following: 2-methyl-4-pyridinyl,2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl,6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl),2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl,2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl,2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl,2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like.

The term "lower-hydroxyalkyl" as used herein, e.g., for one of themeanings for R₁ or R₃ in formula I, means hydroxyl-alkyl radicals havingfrom two to six carbon atoms which can be arranged as straight orbranched chains and at least two carbon atoms of which separate hydroxyand the 1-ring or 3-ring nitrogen atom of the imidazo[4,5-b]pyridinering, illustrated by 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, and thelike.

The term "lower-alkoxyalkyl" as used herein, e.g., for one of themeanings for R₁ or R₃ in formula I, means alkoxyalkyl radicals havingfrom three to six carbon atoms which can be arranged as straight orbranched chains and at least two carbon atoms of which separate theoxygen atom of alkoxyalkyl and the 1-ring or 3-ring nitrogen atom of theimidazo[4,5-b]pyridine ring, illustrated by 2-methoxyethyl,2-ethoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxybutyl,4-ethoxybutyl, 3-ethoxypropyl, 3-n-propoxypropyl, and the like.

The term lower-alkylene designated as Y as part of R₁ or R₃ herein meanslower-alkylene radicals having at least two carbon atoms between itsconnecting linkages and having from two to six carbon atoms which can bearranged as branched or straight chains, illustrated by ##STR4## and thelike.

The compounds of formula I are useful both in the free base form and inthe form of acid-addition salts, and, both forms are within the purviewof the invention. The acid-addition salts are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the base form. The acids which can be used to prepare theacid-addition salts include preferably those which produce, whencombined with the free base, pharmaceutically-acceptable salts, that is,salt whose anions are relatively innocuous to the animal organism inpharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base (I) are not vitiated by sideeffects ascribable to the anions. In practicing the invention, it isconvenient to use the free base form or the hydrochloride salt; however,appropriate pharmaceutically-acceptable salts within the scope of theinvention are those derived from other mineral acids such as hydrobromicacid, sulfuric acid, phosphoric acid and sulfamic acid; and organicacids such as acetic acid, citric acid, lactic acid, tartaric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and thelike, giving the hydrobromide, sulfate, phosphate, sulfamate, acetate,citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compound (I) are prepared eitherby dissolving the free base in aqueous or aqueous-alcohol solution orother suitable solvents containing the appropriate acid and isolatingthe salt by evaporating the solution, or by reacting the free base andacid in an oranic solvent, in which case the salt separates directly orcan be obtained by concentration of the solution.

Although pharmaceutically-acceptable salts of said basic compound (I)are preferred, all acid-addition salts are within the scope of ourinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically-acceptable salt by ionexchange procedures.

The molecular structure of the compound of formula I was assigned on thebasis of evidence provided by infrared, nuclear magnetic resonance andmass spectra, and by the correspondence of calculated and found valuesfor the elementary analysis.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows.

The preparation of 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one (I, Z is O) by reacting 2-R₃NH-3-R₁ NH-5-PY-6-Q-pyridine (II) with urea is conveniently andpreferably carried out by heating the reactants in refluxingdimethylformamide. Alternatively, other suitable inert solvents can beused, e.g., dioxane, nitrobenzene, etc. The reaction usingcarbonyldiimidazole instead of urea is conveniently carried out indimethylformamide at about 35° C. for about one to three hours and thenat about 70° C. to 80° C. for about two to sixteen hours. Thispreparation is illustrated further hereinbelow in Examples G-1 throughG-37.

The preparation of 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-thione (I, Z is S) is carried outby reacting 2-R₃ NH-3-R₁ NH-5-PY-6-Q-pyridine (II) with an alkali metalxanthate, thiourea or thiocarbonyldiimidazole. The reaction using analkali metal xanthate, preferably the sodium or potassium salt, isconveniently run by refluxing the reactants in a mixture of water and alower-alkanol, preferably aqueous ethanol. The reaction using thioureais conveniently run by heating the reactants in refluxingdimethylformamide. The reaction using thiocarbonyldiimidazole isconveniently run at room temperature or slightly above indimethylformamide. This preparation is further illustrated hereinbelowin Examples H-1 through H-11.

The preparation of the intermediate 2-R₃ NH-3-R₁ NH-5-PY-6-Q-pyridines(II), which are disclosed and claimed in copending U.S. patentapplication Ser. No. 135,100, filed Mar. 28, 1980, is presented in thefollowing paragraphs.

The reaction of a 3-nitro-5-PY-6-Q-2(1H)-pyridinone or of a5-PY-6-Q-2(1H)-pyridinone with an inorganic halogenating agent toproduce a 2-halo-3-nitro-5-PY-6-Q-pyridine (III) or2-halo-5-PY-6-Q-pyridine (VII) is preferably carried out by refluxingthe 2(1H)-pyridinone with excess phosphorus oxychloride containing acatalytic amount of dimethylformamide to obtain the 2-chloro compound.Other suitable inorganic halogenating agents include PCl₃, POBr₃, PBr₃,PCl₅, and the like. This reaction is further illustrated below inExamples A-1 through A-17 and B-1 through B-17.

The reaction of the 2-halo compound (III or VII) with ammonia or anamine of the formula R₃ RNH to obtain V or VIII respectively, is run byheating the reactants, preferably under pressure using ammonia or sourcethereof and monomethylamine and at atmospheric pressure using the otherhigher primary amines, R₃ NH₂ or secondary amines, R₃ RNH. The reactionof III or VII with hydrazine is similarly run to obtain thecorresponding 2-hydrazino derivatives, which are readily converted byreduction to the corresponding 2-amines. This reaction is furtherillustrated hereinbelow in Examples C-1 through C-29 and D-1 throughD-9.

The reaction of V to obtain II where R₁ is hydrogen is preferablycarried out by catalytic hydrogenation of V using a suitable catalyst,e.g., 10% palladium-on-charcoal, Raney nickel, and the like. Thisreaction is further illustrated hereinbelow in Examples F-1 throughF-30.

The reaction of VIII with a halogenating agent to produce thecorresponding 3-halo compound (IX) is preferably carried out usingbromine to obtain the 3-bromo compound or phenylphosphoric dichloride toobtain the 3-chloro compound. Optionally, the 3-chloro compound (IX) canbe obtained in two steps by first reacting3-nitro-5-PY-6-Q-2(1H)-pyridinone with phenylphosphoric dichloride toproduce 2,3-dichloro-5-PY-6-Q-pyridine and then selectively reacting thelatter at the more reactive 2-chloro with R₃ RNH to produce IX. Thisreaction is further illustrated hereinbelow in Examples E-1 through E-3.

The reaction of IX with ammonia or an amine of the formula R₁ R'NH toproduce II is carried out by heating the reactants as described above inthe conversion of III to V or VII to VIII. This reaction is furtherillustrated below in Examples F-31 through F-41.

The preparation of the known 1,2-dihydro-2-oxo-5-PY-nicotinic acids byhydrolysis of the corresponding 1,2-dihydro-2-oxo-5-PY-nicotinonitrileis shown in Lesher and Opalka U.S. Pat. No. 4,004,012, issued Jan. 18,1977.

The hydrolysis of 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-nicotinonitrile toproduce 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-PY-nicotinic acid isconveniently run by heating the nitrile on a steam bath with an aqueousmineral acid, e.g., 50% sulfuric acid. This reaction is furtherillustrated below in Examples K-1 through K-11.

The preparation of the intermediate1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)-nicotinonitriles are prepared bythe procedure described in the following three paragraphs; this subjectmatter is disclosed and claimed in copending U.S. patent applicationSer. No. 97,504, filed Nov. 26, 1979 and now abandoned in favor of itscopending continuation-in-part application Ser. No. 198,461, filed Oct.20, 1980.

The preparation of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone byreacting PY-methyl lower-alkyl ketone with dimethylformamidedi-(lower-alkyl)acetal is carried out by mixing the reactants in thepresence or absence of a suitable solvent. The reaction is convenientlyrun at room temperature, i.e., about 20°-25° C., or by warming thereactants up to about 100° C., preferably in a aprotic solvent,conveniently hexamethylphosphoramide because of the method used toprepare the PY-methyl lower-alkyl ketone, as noted below in Example C-1.Other suitable solvents include tetrahydrofuran, dimethylformamide,acetonitrile, ether, benzene, dioxane, and the like. Also the reactioncan be run using no solvent, preferably using an excess ofdimethylformamide di-(lower-alkyl)acetal. This reaction is furtherillustrated hereinbelow in Examples I-1 through I-11.

The intermediate PY-methyl lower-alkyl ketones are generally knowncompounds which are prepared by known methods [e.g., as given in Rec.trav. chim 72, 522 (1953); U.S. Pat. No. 3,133,077 (5-12-64); Bull. Soc.Chim. France 1968, 4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs.81, 120,401a (1974); J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87,6594q (1977); J. Org. Chem. 43, 2286 (1978)].

The reaction of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone withα-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-6-R-nicotinotrile iscarried out preferably by heating the reactants in a suitable solvent inthe presence of a basic condensing agent. The reaction is convenientlyrun using an alkali lower-alkoxide, preferably sodium methoxide orethoxide, in dimethylformamide. In practicing the invention, thereaction was carried out in refluxing dimethylformamide using sodiummethoxide. Alternatively, methanol and sodium methoxide or ethanol andsodium ethoxide can be used as solvent and basic condensing agent,respectively, however, a longer heating period is required. Other basiccondensing agents and solvents include sodium hydride, lithiumdiethylamide, lithium diisopropylamide, and the like, in an aproticsolvent, e.g., tetrahydrofuran, acetonitrile, ethenyl, benzene, dioxane,and the like. This reaction is further illustrated hereinbelow inExamples J-1 through J-11.

The preparation of the intermediate6-(lower-alkyl-3-nitro-5-PY-2(1H)-pyridinones is carried out followingthe procedure described in Example C-1 of U.S. Pat. No. 4,072,746 usingin place of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid in a molarequivalent quantity of the appropriate1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)nicotinic to produce instead of3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone the corresponding6-(lower-alkyl)-3-nitro-5-PY-2(1H)pyridinone. This procedure is furtherillustrated hereinbelow in Example L-1 through L-11.

The preparation of the intermediate6-(lower-alkyl)-5-PY-2(1H)-pyridinones is carried out following thealternative procedure described from line 59 of column 15 to line 2 ofcolumn 16 in Example C-1 of U.S. Pat. No. 4,072,746 using in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile a molar equivalentquantity of the appropriate1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)nicotinonitrile to produce insteadof 5-(4-pyridinyl)-2(1H)-pyridinone the corresponding6-(lower-alkyl)-5-PY-2(1H)-pyridinone. This procedure is furtherillustrated hereinbelow in Examples M-1 through M-11.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 2-HALO-3-NITRO-5-PY-6-Q-PYRIDINES

A-1. 2-Halo-3-nitro-5-(4-pyridinyl)pyridine, alternatively named6-chloro-5-nitro-[3,4'-bipyridine]

A mixture containing 108.5 g. of3-nitro-5-(4-pyridinyl)-2-(1H)-pyridinone, 1250 ml. of phosphorusoxychloride and five drops of dimethylformamide was refluxed for twohours and then allowed to stand at room temperature overnight. Theexcess phosphorus oxychloride was distilled off in vacuo and theremaining material was poured into ice and water. The aqueous mixturewas basified with ammonium hydroxide and stirred for one hour. The solidwas collected and dried to yield 102 g. of2-halo-3-nitro-5-(4-pyridinyl)pyridine.

Following the procedure of Example A-1 but using in place of3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone a molar equivalent quantity ofthe appropriate 3-nitro-5-PY-6-Q-2(1H)-pyridinone (preparation of thesecompounds where Q is lower-alkyl is given hereinbelow in Examples L-1through L-11, it is contemplated that the corresponding2-chloro-3-nitro-5-PY-6-Q-pyridines of Examples A-2 through A-16 can beobtained.

A-2. 2-Chloro-3-nitro-5-(3-pyridinyl)pyridine.

A-3. 2-Chloro-3-nitro-5-(2-methyl-3-pyridinyl)pyridine.

A-4. 2-Chloro-3-nitro-5-(5-methyl-3-pyridinyl)pyridine.

A-5. 2-Chloro-3-nitro-5-(3-ethyl-4-pyridinyl)pyridine.

A-6. 2-Chloro-6-methyl-3-nitro-5-(4-pyridinyl)pyridine.

A-7. 2-Chloro-6-ethyl-3-nitro-5-(4-pyridinyl)pyridine.

A-8. 2-Chloro-6-methyl-3-nitro-5-(3-pyridinyl)pyridine.

A-9. 2-Chloro-3-nitro-6-n-propyl-5-(4-pyridinyl)pyridine.

A-10. 2-Chloro-3-nitro-6-isopropyl-5-(4-pyridinyl)pyridine.

A-11. 6-n-Butyl-2-chloro-3-nitro-5-(4-pyridinyl)pyridine.

A-12. 2-Chloro-6-isobutyl-3-nitro-5-(4-pyridinyl)pyridine.

A-13. 2-Chloro-3-nitro-5-(4-pyridinyl)-6-tert.-butylpyridine.

A-14. 2-Chloro-3-nitro-5-n-pentyl-5-(4-pyridinyl)pyridine.

A-15. 2-Chloro-6-ethyl-5-(2-methyl-4-pyridinyl)-3-nitropyridine.

A-16. 2-Chloro-6-ethyl-3-nitro-5-(3-pyridinyl)pyridine.

Following the procedure of Example A-1 but using in place of phosphorusoxychloride a molar equivalent quantity of phosphorus oxybromide orphosphorus tribomide, it is contemplated that the compound of ExampleA-17 can be obtained.

A-17. 2-Bromo-3-nitro-5-(4-pyridinyl)pyridine.

B. 2-HALO-5-PY-6-Q-PYRIDINES

B-1. 2-Chloro-5-(4-pyridinyl)pyridine, alternatively named6-chloro-[3,4'-bipyridine]

A mixture containing 105 g. of 5-(4-pyridinyl)-2(1H)-pyridinone and 1liter of phosphorus oxychloride was heated on a steam bath for two hoursand then allowed to stand at room temperature overnight. The excessphsophorus oxychloride was distilled off in vacuo and the remainingmaterial poured into ice. The aqueous mixture was made weakly basic withammonium hydroxide. The precipitate was collected, washed with water anddried in vacuo at 70° C. to yield 108 g. of2-chloro-5-(4-pyridinyl)pyridine.

Following the above procedure but using in place of phosphorusoxychloride a molar equivalent quantity of phosphorus oxybromide orphosphorus tribromide, it is contemplated that the correspondingcompound of Example B-2 can be obtained.

B-2. 2-Bromo-5-(4-pyridinyl)pyridine.

Following the procedure described in Example B-1 but using in place of5-(4-pyridinyl)-2(1H)pyridinone a molar equivalent quantity of thecorresponding 5-PY-6-Q-2(1H)-pyridinone (preparation of these compoundswhere Q is lower-alkyl is given hereinbelow in Examples M-1 throughM-11), it is contemplated that the corresponding2-chloro-5-PY-6-Q-pyridines of Examples B-3 through B-17 can beobtained.

B-3. 2-Chloro-5-(3-pyridinyl)pyridine.

B-4. 2-Chloro-5-(2-methyl-3-pyridinyl)pyridine.

B-5. 2-Chloro-5-(5-methyl-3-pyridinyl)pyridine.

B-6. 2-Chloro-5-(3-ethyl-4-pyridinyl)pyridine.

B-7. 2-Chloro-6-methyl-5-(4-pyridinyl)pyridine.

B-8. 2-Chloro-6-ethyl-5-(4-pyridinyl)pyridine.

B-9. 2-Chloro-6-methyl-5-(4-pyridinyl)pyridine.

B-10. 2-Chloro-6-n-propyl-5-(4-pyridinyl)pyridine.

B-11. 2-Chloro-6-isopropyl-5-(4-pyridinyl)pyridine.

B-12. 6-n-Butyl-2-chloro-5-(4-pyridinyl)pyridine.

B-13. 2-Chloro-6-isobutyl-5-(4-pyridinyl)pyridine.

B-14. 2-Chloro-5-(4-pyridinyl)-6-tert.-butylpyridine.

B-15. 2-Chloro-6-n-pentyl-5-(4-pyridinyl)pyridine.

B-16. 2-Chloro-6-ethyl-5-(2-methyl-4-pyridinyl)pyridine.

B-17. 2-Chloro-6-ethyl-5-(3-pyridinyl)pyridine.

C. 3-NITRO-5-PY-6-Q-PYRIDIN-2-AMINES

C-1. 3-Nitro-5-(pyridinyl)pyridin-2-amine, alternatively named5-nitro-[3,4'-bipyridin]-6-amine

A mixture containing 27 g. of 2-chloro-3-nitro-5-(4-pyridinyl)pyridineand 600 ml. of ammonium hydroxide was autoclaved at 100° C. and 150p.s.i. for eight hours. The solid was collected and dried in vacuo at70° C. The filtrate was concentrated in vacuo to about 200 ml. andcooled; the separated solid was collected and dried in vacuo at 70° C.The solids were combined, recrystallized twice from dimethylformamide,washed successively with ethanol and ether and dried in vacuo at 70° C.to yield 15 g. of 3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p. 247°-249°C. with decomposition.

Optionally, the corresponding3-nitro-5-(4-pyridinyl)pyridine-2-hydrazine was prepared as follows: Amixture containing 10 g. of 2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 50ml. of hydrazine hydrate and 50 ml. of ethanol was refluxed for one hourand the ethanol and excess hydrazine-hydrate distilled off in vacuo. Theresidue was dissolved in water and reprecipitated with isopropylalcohol, collected, washed with isopropyl alcohol and dried in vacuo at70° C. to yield 7 g. of 3-nitro-5-(4-pyridinyl)pyridin-2-hydrazine.

C-2. N-Methyl-3-nitro-5-(4-pyridinyl)pyridine-2-amine, alternativelynamed N-methyl-5-nitro-[3,4'-bipyridin]-6-amine

A mixture containing 47 g. of 2-chloro-3-nitro-5-(4-pyridinyl)pyridine,300 ml. of 40% aqueous methylamine and 300 ml. of ethanol was autoclavedfor six hours at 100° C. The solid was filtered off and the filtrate wasconcentrated in vacuo to a volume of about 200 ml. and then cooled.About 2 g. of dark solid was filtered off and the filtrate was heated invacuo to dryness. The residue was dissolved in about 250 ml. of waterand the aqueous solution was extracted with several portions ofchloroform. The chloroform extracts were combined, back-washed withwater, dried over anhydrous sodium sulfate, treated with decolorizingcharcoal and filtered. The filtrate was stripped in vacuo to yield, as adark oil, 18.5 g. ofN-methyl-3-nitro-5-(4-pyridinyl)-2-pyridine-2-amine.

C-3. N-Ethyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine, alternatively namedN-ethyl-5-nitro-[3,4'-bipyridin]-6-amine

A mixture containing 23.56 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 80.5 ml. of 70% aqueousethylamine and 1 liter of 95% ethanol was heated with stirring on asteam bath for over sixteen hours and then concentrated in vacuo toremove solvent and excess aqueous ethylamine. The residue wasrecrystallized from isopropyl alcohol (final volume of 200 ml.) anddried in a vacuum oven at 60° C. for sixteen hours to yield 16.27 g. ofN-ethyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p. 129°-132° C.

C-4. N-(2-Hydroxyethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine,alternatively named N-(2-hydroxyethyl)-5-nitro-[3,4'-bipyridin]-6-amine

A mixture containing 23.56 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 63.0 ml. of 2-aminoethanol and1000 ml. of ethanol was refluxed with stirring over sixteen hours andthe filtrate concentrated to one-half of its volume in vacuo. Theseparated solid was collected to yield 13 g. of orange-brown solid. Thefiltrate was concentrated in vacuo to less than 200 ml. and was dilutedwith water. The resulting precipitate was collected to yield another 7g. of brown solid which was recrystallized from isopropyl alcohol toyield orange-brown prisms; this orange-brown material was combined withthe above 13 g. of orange-brown solid and the combined material wasrecrystallized from isopropyl alcohol (600 ml. final volume) to yield,as an orange-brown solid, 12.42 g. ofN-(2-hydroxyethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p.188°-190° C. after sintering about 180° C. Concentration of the filtrateto about 250 ml. yielded additional orange-brown solid, which wascollected, dried and found to melt at 183°-186° C.

C-5. N-(2-Dimethylaminoethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine,alternatively namedN-(2-dimethylaminoethyl)-5-nitro-[3,4'-bipyridin]-6-amine

A mixture containing 11.77 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 8.6 ml. of2-dimethylaminoethylamine and 500 ml. of ethanol was refluxed withstirring over twenty-two hours, the hot solution filtered and thefiltrate concentrated in vacuo to remove the solvent. The residue wasrecrystallized from 1000 ml. of cyclohexane to yield some insolublebrown oil, 5.6 g. of yellow solidN-(2-dimethylaminoethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p.110°-112° C., and from the filtrate, another 1.2 g. of yellow solidproduct, m.p. 110°-112° C., sintering at 107° C. The insoluble brown oilwas taken up in methanol and was concentrated several times withcyclohexane; the insoluble material was filtered off and the filtrateconcentrated to less than 300 ml. Some insoluble brown gum was filteredoff and the filtrate on cooling yielded another 2.14 g. of yellow solidproduct, m.p. 109°-111° C.

C-6. N-(2-Diethylaminoethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine,alternatively namedN-(2-diethylaminoethyl)-5-nitro-[3,4'-bipyridin]-6-amine

A mixture containing 47.13 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 70.8 ml. of2-diethylaminoethylamine and 1.4 liters of ethanol was refluxed withstirring for over four hours. The ethanolic solution of the reactionmixture was filtered through diatomaceous earth (no insoluble material)and the filtrate was diluted with 2 liters of water and the resultingaqueous mixture chilled. The precipitated yellow-orange solid wascollected and dried in vacuo at 90° C. for over sixteen hours to yield43.2 g. of orange-yellow solidN-(2-diethylaminoethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p.100.5°-102° C., after sintering at 100° C. Another 1.75 g. ofyellow-orange solid product, m.p. 100°-101° C., after sintering at 99°C., was obtained from the filtrate.

C-7. N-(3-Dimethylaminopropyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine

A mixture containing 47.13 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 63.6 ml. of3-dimethylaminopropylamine and 700 ml. of ethanol was refluxed withstirring for over five hours and then allowed to stand overnight at roomtemperature. The solution was then concentrated in vacuo to a volume ofabout 250 ml. and the resulting concentrated solution was diluted with800 ml. of water. The separated solid was collected and dried in vacuoat 90° C. for over sixty hours to yield 49.4 g. of orange-brown solid,m.p. 94°-96° C., after sintering about 80° C. The solid was dissolved inabout 250 ml. of methanol and the hot solution diluted with water andcooled. The separated yellow solid was air-dried for over forty-eighthours, to yield 45.5 g. ofN-(3-dimethylaminopropyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p.95.6° C., after softening at 90° C. and sintering at 94° C.

C-8. N,N-Dimethyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine

A mixture containing 25.92 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 62 g. of 40% aqueousdimethylamine and 600 ml. of 95% ethanol was autoclaved at 100° C. forover eight hours. The solvent was distilled off in vacuo and theremaining yellow solid residue was recrystallized from isopropyl alcohol(300 ml.)-water to yield, after drying at 90° C. in vacuo over potassiumhydroxide for sixteen hours, 24.46 g. ofN,N-dimethyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p. 135°-137° C.

C-9. N-[2-(4-Morpholinyl)ethyl]-3-nitro-5-(4-pyridinyl)pyridin-2-amine

A mixture containing 30.48 g. of2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 33.7 g. of 97%2-(4-morpholinyl)ethylamine and 450 ml. of ethanol was refluxed withstirring for over five hours and the reaction mixture allowed to cool.The separated product was collected and dried in vacuo over four hoursat 90° C. to yield 36.0 g. ofN-[2-(4-morpholinyl)ethyl]-3-nitro-5-(4-pyridinyl)pyridin-2-amine, m.p.140°-141° C., after sintering at 139° C. Another 3.73 g. of product,m.p. 134°-136° C. after sintering at 133° C. was obtained byconcentrating the filtrate to a volume of about 100 ml., adding water,filtering the precipitate and drying it as above.

Following the procedure described in Example C-1 or C-3 but using inplace of 2-chloro-3-nitro-5-(4-pyridinyl)pyridine and ammonium hydroxideor ethylamine corresponding molar equivalent quantities respectively ofthe appropriate 3-nitro-5-PY-6-Q-pyridine and ammonium hydroxide, R₃ NH₂or RRNH, it is contemplated that the 3-nitro-5-PY-6-Q-pyridin-2-aminesof Examples C-10 through C-29 can be obtained.

C-10. N-n-Propyl-3-nitro-5-(3-pyridinyl)pyridine-2-amine.

C-11. N-Isopropyl-3-nitro-5-(2-methyl-5-pyridinyl)pyridin-2-amine.

C-12. N-n-Butyl-3-nitro-5-(5-methyl-3-pyridinyl)pyridin-2-amine.

C-13. N-n-Amyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-14. N-n-Hexyl-3-nitro-5-(3-pyridinyl)pyridin-2-amine.

C-15. N-Ethyl-5-methyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-16. N,N-Diethyl-6-ethyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-17. N,N-Dimethyl-6-methyl-3-nitro-5-(3-pyridinyl)pyridin-2-amine.

C-18. 3-Nitro-5-n-propyl-5-(4-pyridinyl)pyridin-2-amine.

C-19. 3-Nitro-6-isopropyl-5-(4-pyridinyl)pyridin-2-amine.

C-20. 6-n-Butyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-21. 6-Isobutyl-3-nitro-5-(4-pyridinyl)pyridine-2-amine.

C-22. 3-Nitro-5-(4-pyridinyl)-6-tert.-butylpyridin-2-amine.

C-23. 3-Nitro-6-n-pentyl-5-(4-pyridinyl)pyridin-2-amine.

C-24.N-(2-Ethoxyethyl)-6-ethyl-5-(2-methyl-4-pyridinyl)-3-nitropyridin-2-amine.

C-25. N-(2-Methoxyethyl)-6-ethyl-3-nitro-5-(3-pyridinyl)pyridin-2-amine.

C-26. N-(3-Methoxypropyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-27. N-(2-Hydroxyethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-28. N-(3-Hydroxypropyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

C-29. N-(2,3-Dihydroxypropyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine.

D. 5-PY-6-Q-PYRIDIN-2-AMINES

D-1. 5-(4-Pyridinyl)pyridin-2-amine, alternatively named[3,4'-bipyridin]-6-amine

A mixture containing 48 g. of 2-chloro-5-(4-pyridinyl)pyridine and 700ml. of ammonium hydroxide was heated in an autoclave at 150° C. and 200p.s.i. for sixteen hours. The solid was collected, washed with water anddried. The filtrate was distilled in vacuo to remove the excess ammoniumhydroxide and the remaining residue was combined with the above solidand the combined material was recrystallized from water and dried invacuo at 70° C. to yield 29 g. of 5-(4-pyridinyl)pyridin-2-amine, m.p.192°-195° C.

D-2. N-Methyl-5-(4-pyridinyl)pyridin-2-amine

A mixture containing 52 g. of 2-chloro-5-(4-pyridinyl)pyridine and 250ml. of 40% aqueous methylamine was heated in an autoclave at 150° C. and300 p.s.i. for fifteen hours. The reaction mixture was then distilled invacuo to remove the excess water and methylamine and the residue wasslurried up in water. The solid was collected, washed with water anddried and then recrystallized from acetonitrile, washed with ether anddried in vacuo at 70° C. to yield 25 g. ofN-methyl-5-(4-pyridinyl)pyridin-2-amine, m.p. 152°-154° C.

D-3. N,N-Dimethyl-5-(4-pyridinyl)pyridin-2-amine

A mixture containing 25 g., of 2-chloro-5-(4-pyridinyl)pyridine and 110ml. of 40% aqueous dimethylamine was autoclaved at 150° C. and 100p.s.i. for fifteen hours. The solid was collected, washed with water,dried, recrystallized from 50% aqueous ethanol, dried in vacuo at 70° C.to yield 18.5 g. of N,N-dimethyl-5-(4-pyridinyl)pyridin-2-amine, m.p.176°-178° C.

Following the procedure described in Example D-2 but using in place ofmethylamine a molar equivalent quantity of R₃ NH₂, it is contemplatedthat the N-R₃ -5-(4-pyridinyl)pyridin-2-amines of Examples D-4 throughD-9 can be obtained.

D-4. N-Ethyl-5-(4-pyridinyl)pyridin-2-amine.

D-5. N-(n-Propyl)-5-(4-pyridinyl)pyridin-2-amine.

D-6. N-(Isobutyl)-5-(4-pyridinyl)pyridin-2-amine.

D-7. N-(2-Methoxyethyl)-5-(4-pyridinyl)pyridin-2-amine.

D-8. N-(2-Hydroxyethyl)-5-(4-pyridinyl)pyridin-2-amine.

D-9. N-(2-Dimethylaminoethyl)-5-(4-pyridinyl)pyridin-2-amine.

E. 3-HALO-5-PY-6-Q-PYRIDIN-2-AMINES

E-1. 3-Bromo-5-(4-pyridinyl)pyridin-2-amine, optionally named5-bromo-[3,4--bipyridin]-6-amine

A solution containing 17 g. of 5-(4-pyridinyl)pyridin-2-amine in 200 ml.of acetic acid warmed to 70° C. was treated dropwise with 17.6 g. ofbromine. The reaction mixture was heated at about 70°-75° C. for thirtyminutes, allowed to cool and then diluted with ether. The precipitatewas collected, washed with ether and dried. The solid was dissolved inwater and the aqueous solution was basified with 2 N aqueous potassiumhydroxide solution. The precipitate was collected, washed with water anddried and then recrystallized from ethanol and dried in vacuo at 70° C.to yield 14.5 g. of 3-bromo-5-(4-pyridinyl)pyridin-2-amine, m.p. 197° C.A sample for analysis was recrystallized twice from ethanol, the secondtime using decolorizing charcoal and then washing with ether and dryingin vacuo at 70° C. to yield 8 g. of the product, m.p. 198°-199° C.

E-2. N-Methyl-3-bromo-5-(4-pyridinyl)pyridin-2-amine

To a solution containing 9.3 g. ofN-methyl-5-(4-pyridinyl)pyridin-2-amine in 100 ml. of acetic acid atroom temperature was added dropwise with stirring 8.8 g. of bromine. Thereaction mixture was stirred at room temperature for one hour. The solidwas collected, washed with ether and dried. The solid was dissolved inwater and the aqueous solution was basified with ammonium hydroxide withstirring. The solid was collected, washed with water and dried. Thesolid was recrystallized from acetonitrile using decolorizing charcoal,washed with ether and dried in vacuo at 70° C. to yield 8 g. ofN-methyl-3-bromo-5-(4-pyridinyl)pyridin-2-amine, m.p. 165°-167° C.

E-3. 3-Chloro-5-(4-pyridinyl)pyridin-2-amine

A mixture containing 22 g. of3-chloro-5-(4-pyridinyl)pyridine-2-hydrazine, 300 ml. ofdimethylformamide and 2 g. of Raney nickel in a Parr apparatus wasshaken with hydrogen under catalytic hydrogenation conditions for threehours. When a tlc analysis indicated the presence of starting material,another 2 g. of Raney nickel was added and the hydrogenation wascontinued at 45° C. for four hours. The solvent was distilled off invacuo and the remaining residue was recrystallized once from methanoland a second time from ethanol using decolorizing charcoal. The solidwas dissolved in 6 N hydrogen chloride and isopropyl alcohol was added.The mixture was cooled and the separated product was collected, washedsuccessively with isopropyl alcohol and ether and dried in vacuo at 70°C. to yield 2.5 g. of 3-chloro-5-(4-pyridinyl)pyridin-2-aminedihydrochloride monohydrate, m.p. 283°-286° C.

The above intermediate 3-chloro-5-(4-pyridinyl)pyridine-2-hydrazine wasprepared in two steps as follows: A mixture containing 31 g. of3-nitro-5-(4-pyridinyl)-2(1H)-2-pyridinone, and 150 ml. ofphenylphosphonic dichloride was heated on an oil bath at 210°-220° C.for two hours and then allowed to cool. The reaction mixture was pouredinto ice and water and the aqueous mixture was basified with ammoniumhydroxide while stirring. The separated product was collected, washedwith water and dried. It was then recrystallized from isopropyl alcoholand dried to yield 17 g. of 2,3-dichloro-5-(4-pyridinyl)pyridine, m.p.274°-275° C. with decomposition. A mixture containing 9 g. of2,3-dichloro-5-(4-pyridinyl)pyridine, 50 ml. of 100% hydrazine hydrateand 50 ml. of ethanol was refluxed for one hour and then cooled. Theseparated hydrazine hydrochloride was filtered off and the filtrate washeated in vacuo to remove the solvent to yield 7 g. of3-chloro-5-(4-pyridinyl)pyridine-2-hydrazine in free base form. Saidfree base form was recrystallized from dimethylformamide and thendissolved in 6 N hydrogen chloride and the solution treated withisopropyl alcohol. The mixture was cooled and the separated product wascollected, washed with ether and dried in vacuo at 70° C. to yield 5 g.of 3-chloro-5-(4-pyridinyl)pyridine-2-hydrazine dihydrochloride, m.p.298°-300° C. with decomposition.

F. 2-R₁ NH-3-R₃ NH-5-PY-6-Q-PYRIDINES

F-1. 2,3-Diamino-5-(4-pyridinyl)pyridine, alternatively named[3,4'-bipyridin]-5,6-diamine

A mixture containing 7 g. of3-nitro-5-(4-pyridinyl)pyridine-2-hydrazine, 150 ml. ofdimethylformamide and 2 g. of Raney nickel was shaken in a Parrapparatus with hydrogen under pressure at 45° C. for twelve hours. Thereaction mixture was filtered and the filtrate heated in vacuo to removethe solvent. The residue was shaken well with water and the solid againcollected. The solid was crystallized from ethanol, dissolved in 6 Nhydrogen chloride and reprecipitated with ethyl alcohol and the mixturecooled. The product was collected, washed successively with ethanol andether and dried in vacuo at 70° C. to yield 3 g. of2,3-diamino-5-(4-pyridinyl)pyridine dihydrochloride, m.p. >300° C.

Alternatively, the above product can be prepared by reducing thecorresponding 3-nitro-5-(4-pyridinyl)pyridin-2-amine as follows: amixture containing 27 g. of 3-nitro-5-(4-pyridinyl)pyridin-2-amine, 200ml. of dimethylformamide and 2 g. of 10% palladium-on-charcoal wascatalytically hydrogenated in a Parr apparatus for three and one-halfhours at room temperature. The reaction mixture was filtered and thefiltrate heated in vacuo to remove the solvent. The residue was combinedwith material obtained in another run starting with 10 g. of3-nitro-5-(4-pyridinyl)pyridin-2-amine and the combined material wasrecrystallized from ethanol, washed with ether and dried in vacuo at 70°C. to yield 14 g. of 2,3-diamino-5-(4-pyridinyl)pyridine.

F-2. 3-Amino-2-methylamino-5-(4-pyridinyl)pyridine

A mixture containing 21 g. of2-methylamino-3-nitro-5-(4-pyridinyl)pyridine, 200 ml. of ethanol and 2g. of 10% palladium-on-charcoal was shaken under catalytic hydrogenationconditions in a Parr apparatus at room temperature for three hours. Thereaction mixture was filtered and the solvent distilled off in vacuo.The remaining solid was recrystallized from acetonitrile, washed withether and dried in vacuo at 70° C. to yield3-amino-2-methylamino-5-(4-pyridinyl)pyridine (alternatively named N⁶-methyl-[3,4'-bipyridine]-5,6-diamine), m.p. 184°-187° C.

F-3. 3-Amino-2-ethylamino-5-(4-pyridinyl)pyridine

A mixture containing 18.11 g. of2-ethylamino-3-nitro-5-(4-pyridinyl)pyridine, 250 ml. of ethanol and 2.0g. of 10% palladium-on-charcoal was shaken in a Parr apparatus undercatalytic hydrogenation conditions for twenty-one hours at roomtemperature. The reaction mixture was filtered and the filtrate washeated in vacuo to remove the solvent. The remaining residue wasrecrystallized from acetonitrile using decolorizing charcoal (finalvolume of 300 ml.) and dried at 70° C. in a vacuum oven for sixteenhours to produce 8.55 g. of compound melting at 179°-183° C. A secondcrop of 4.36 g. of material, m.p. 179°-183° C. was obtained byconcentrating the filtrate to 100 ml. A 4.72 g. portion of this productwas combined with an 8.37 g. portion of this product was combined withan 8.37 g. portion of product obtained in another run and the combinedmaterial was recrystallized from acetonitrile (final volume of 200 ml.)and dried in a vacuum oven at 90° C. over sixty hours to yield a firstcrop of 7.92 g. of 3-amino-2-ethylamino-5-(4-pyridinyl)pyridine, m.p.183°-186° C. and a second crop of 3.73 g. of product, m.p. 182°-186° C.

F-4. 3-Amino-2-(2-hydroxyethylamino)-5-(4-pyridinyl)pyridine

A mixture containing 11.93 g. of2-(2-hydroxyethylamino)-3-nitro-5-(4-pyridinyl)pyridine, 250 ml. ofethanol and 2 g. of 10% palladium-on-charcoal was catalyticallyhydrogenated by shaking in a Parr apparatus at room temperature for overfour hours. The reaction mixture was filtered to remove the catalyst andthe filtrate was concentrated in vacuo to remove the solvent. Theremaining solid residue was recrystallized from acetonitrile (finalvolume of 350 ml.) and dried in a vacuum oven at 90° C. for twenty hoursto yield 8.45 g. of3-amino-2-(2-hydroxyethylamino)-5-(4-pyridinyl)pyridine, m.p.190°-191.5° C.

F-5. 3-Amino-2-(2-dimethylaminoethylamino)-5-(4-pyridinyl)pyridine

A mixture containing 18.26 g. of2-(2-dimethylaminoethylamino)-3-nitro-5-(4-pyridinyl)pyridine, 250 ml.of ethanol and 2.0 g. of 10% palladium-on-charcoal was hydrogenated byshaking in a Parr apparatus under catalytic hydrogenation conditions forseventy-two minutes at room temperature. The catalyst was filtered offand the filtrate was distilled in vacuo to remove the solvent. Theresidue was recrystallized from acetonitrile (final volume of 150 ml.)and dried at 70° C. in a vacuum oven over sixty hours to yield 13.4 g.of 3-amino-2-(2-dimethylaminoethylamino)-5-(4-pyridinyl)pyridine, m.p.138°-141° C.

F-6. 3-Amino-2-(2-diethylaminoethylamino)-5-(4-pyridinyl)pyridine

A mixture containing 13.15 g. of2-(2-diethylaminoethylamino)-3-nitro-5-(4-pyridinyl)pyridine, 250 ml. ofethanol and 2 g. of 10% palladium-on-charcoal was shaken in a Parrapparatus under catalytic hydrogenation conditions for over one andthree-fourth hours at room temperature. The catalyst was filtered offand the filtrate was concentrated in vacuo to remove the solvent. Theresidue was recrystallized from 300 ml. of cyclohexane and dried at 90°C. in a vacuum oven for sixteen hours to yield 10.11 g. of3-amino-2-(2-diethylaminoethylamino)-5-(4-pyridinyl)pyridinemonohydrate, m.p. 104°-106° C.

F-7. 3-Amino-2-(3-dimethylaminopropylamino)-5-(4-pyridinyl)pyridine

A mixture containing 22.6 g. of2-(3-dimethylaminopropylamino)-3-nitro-5-(4-pyridinyl)pyridine, 250 ml.of ethanol and 2.0 g. of 10% palladium-on-charcoal was catalyticallyhydrogenated in a Parr apparatus for one and three-fourth hours at roomtemperature. The catalyst was filtered off and the filtrate was combinedwith the corresponding filtrate of an identical run except for a threehour hydrogenation period and the combined filtrates were concentratedin vacuo to remove the solvent. The residue was dissolved in hotacetonitrile (final volume of 200 ml.) and cooled. When no solidseparated the acetonitrile solution was diluted to a volume of 500 ml.and this solution was treated with decolorizing charcoal, filtered andthe filtrate concentrated to a volume of 200 ml. The resulting solutionchilled. The separated product was collected and dried in a vacuum ovenat 90° C. for sixteen hours to yield 37 g. of3-amino-2-(3-dimethylaminopropylamino)-5-(4-pyridinyl)pyridine, m.p.137°-138° C.

F-8. 3-Amino-2-dimethylamino-5-(4-pyridinyl)pyridine

A mixture containing 24.43 g. of2-dimethylamino-3-nitro-5-(4-pyridinyl)pyridine, 250 ml. of ethanol and2 g. of palladium-on-charcoal was shaken in a Parr apparatus undercatalytic hydrogenation conditions for three hours at room temperature.The catalyst was filtered off and the filtrate was distilled in vacuo toremove the solvent. The residue was recrystallized twice fromacetonitrile (100 ml. and 250 ml., respectively) and dried at 90° C. ina vacuum oven over sixty hours to yield 10.52 g. of3-amino-2-dimethylamino-5-(4-pyridinyl)pyridine, m.p. 190°-194° C.

F-9. 2-Amino-3-methylamino-5-(4-pyridinyl)pyridine

A mixture containing 33 g. of 2-amino-3-bromo-5-(4-pyridinyl)pyridine,700 ml. of 40% aqueous methylamine, a pinch of copper-bronze metal and apinch of cupric sulfate pentahydrate was autoclaved at 160° C. for sixtyhours. The reaction mixture was filtered and the filtrate distilled invacuo to remove the excess aqueous methylamine. The residue was slurriedup in a minimum amount of cold water and the solid collected and dried.The solid was recrystallized twice from dimethylformamide, washedsuccessively with ethanol and ether and dried in vacuo at 70° C. toyield 4 g. of 2-amino-3-methylamino-5-(4-pyridinyl)pyridine, m.p.282°-285° C.

F-10. 3-Amino-2-[2-(4-morpholinyl)ethylamino]-5-(4-pyridinyl)pyridine

A mixture containing 16.34 g. of2-[2-(4-morpholinyl)ethylamino]-3-nitro-5-(4-pyridinyl)pyridine, 250 ml.of ethanol and 2 g. of 10% palladium-on-charcoal was shaken in a Parrapparatus under catalytic hydrogenation conditions at room temperaturefor five hours. The catalyst was filtered off and the filtrate wasconcentrated in vacuo to remove the solvent. The residue wasrecrystallized from ethanol (80 ml.)-water and dried at 80° C. in avacuum oven for eight hours and then redried at 90° C. in a vacuum ovenfor eighteen hours, to yield 9.79 g. of3-amino-2-[2-(4-morpholinyl)ethylamino]-5-(4-pyridinyl)pyridine, m.p.122°-125° C.

Following the procedure described in Example F-1 or F-2 but using inplace of 3-nitro-5-(4-pyridinyl)pyridin-2-amine orN-methyl-3-nitro-5-(4-pyridinyl)pyridin-2-amine a molar equivalentquantity of the appropriate 2-R₃ NH (or RRN)-3-nitro-5-PY-6-Q-pyridine,it is contemplated that the corresponding 3-amino-2-(R₃ NH orRRN)-5-PY-6-Q-pyridines of Examples F-11 through F-30 can be obtained.

F-11. 3-Amino-2-n-propylamino-5-(3-pyridinyl)pyridine.

F-12. 3-Amino-2-isopropylamino-5-(2-methyl-5-pyridinyl)pyridine.

F-13. 3-Amino-2-n-butylamino-5-(5-methyl-3-pyridinyl)pyridine.

F-14. 3-Amino-2-n-amylamino-5-(4-pyridinyl)pyridine.

F-15. 3-Amino-2-n-hexylamino-5-(3-pyridinyl)pyridine.

F-16. 3-Amino-6-methyl-5-(4-pyridinyl)pyridine.

F-17. 3-Amino-6-ethyl-2-diethylamino-5-(4-pyridinyl)pyridine.

F-18. 3-Amino-2-dimethylamino-6-methyl-5-(3-pyridinyl)pyridine.

F-19. 3-Amino-6-n-propyl-5-(4-pyridinyl)pyridine.

F-20. 3-Amino-6-isopropyl-5-(4-pyridinyl)pyridine.

F-21. 3-Amino-6-n-butyl-5-(4-pyridinyl)pyridine.

F-22. 3-Amino-6-isobutyl-5-(4-pyridinyl)pyridine.

F-23. 3-Amino-5-(4-pyridinyl)-6-tert.-butylpyridine.

F-24. 3-Amino-6-n-pentyl-5-(4-pyridinyl)pyridine.

F-25.3-Amino-2-(2-ethoxyethylamino)-6-ethyl-5-(2-methyl-4-pyridinyl)pyridine.

F-26. 3-Amino-6-ethyl-2-(2-methoxyethylamino)-5-(3-pyridinyl)pyridine.

F-27. 3-Amino-2-(3-methoxypropylamino)-5-(4-pyridinyl)pyridine.

F-28. 3-Amino-2-(2-hydroxyethylamino)-6-methyl-5-(4-pyridinyl)pyridine.

F-29. 3-Amino-2-(3-hydroxypropylamino)-5-(4-pyridinyl)pyridine.

F-30. 3-Amino-2-(2,3-dihydroxypropylamino)-5-(4-pyridinyl)pyridine.

Following the procedure described in Example F-9 but using in place ofmethylamine a molar equivalent quantity of the appropriate R₁ NH₂ orR'R'NH, it is contemplated that the corresponding 2-amino-3-R₁ NH (orR'R'N)-5-(4-pyridinyl)pyridines of Examples F-31 through F-40 can beobtained.

F-31. 2-Amino-3-ethylamino-5-(4-pyridinyl)pyridine.

F-32. 2-Amino-3-n-propylamino-5-(4-pyridinyl)pyridine.

F-33. 2-Amino-3-isopropylamino-5-(4-pyridinyl)pyridine.

F-34. 2-Amino-3-n-butylamino-5-(4-pyridinyl)pyridine.

F-35. 2-Amino-3-(2-hydroxyethylamino)-5-(4-pyridinyl)pyridine.

F-36. 2-Amino-3-(2,3-dihydroxypropylamino)-5-(4-pyridinyl)pyridine.

F-37. 2-Amino-3-(3-methoxypropylamino)-5-(4-pyridinyl)pyridine.

F-38. 2-Amino-3-(2-ethoxyethylamino)-5-(4-pyridinyl)pyridine.

F-39. 2-Amino-3-(2-dimethylaminoethylamino)-5-(4-pyridinyl)pyridine.

F-40. 2-Amino-3-(3-diethylaminopropylamino)-5-(4-pyridinyl)pyridine.

F-41. 2-Amino-3-[2-(4-morpholinyl)ethylamino]-5-(4-pyridinyl)pyridine.

G. 1-R₁ -3-R₃ -6-PY-5-Q-2H-IMIDAZO[4,5-b]PYRIDIN-3-ONES

G-1. 1,3-Dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 20 g. of 2,3-diamino-5-(4-pyridinyl)pyridinedihydrochloride, 28 g. of urea and 200 ml. of dimethylformamide wasrefluxed for two hours and then allowed to stand at room temperatureovernight. The reaction mixture was poured into a mixture of ice andwater and the resulting solid was collected, washed with water anddried. The solid was dissolved in 200 ml. of hot 6 N hydrochloric acid,the solution treated with decolorizing charcoal and filtered, and thefiltrate poured into a rapidly stirred liter of ethanol. The resultingmixture was cooled. The separated solid was collected, washedsuccessively with ethanol and ether, and then dried. The solid was thenrecrystallized from water using decolorizing charcoal, washedsuccessively with ethanol and ether and dried in vacuo at 70° C. toyield 6.5 g. of1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-onehydrochloride, m.p. >300° C.

G-2. 1,3-Dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 7 g. of3-amino-2-methylamino-5-(4-pyridinyl)pyridine, 6 g. of urea and 100 ml.of dimethylformamide was refluxed for two hours, cooled and then pouredinto a mixture of ice and water. The separated solid was collected,washed with water and dried. The solid was recrystallized twice fromdimethylformamide, washed successively with ethanol and ether and driedin vacuo at 70° C. to yield 5 g. of1,3-dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one,m.p. >300° C.

G-3. 3-Ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 8.57 g. of3-amino-2-ethylamino-5-(4-pyridinyl)pyridine, 9.73 g. ofcarbonyldiimidazole and 200 ml. of dimethylformamide was stirred in awater bath at 35° C. for over ninety minutes, at room temperatureovernight and then heated to 80° C. for thirty minutes. To the mixturewas added 15 ml. of water and the solution was treated with decolorizingcharcoal and filtered. The filtrate was concentrated in vacuo to removethe liquid and the residue was recrystallized from acetonitrile (finalvolume of 140 ml.) and dried at 90° C. in a vacuum oven for sixteenhours to yield 5.15 g. of dark green solid. Another 2.56 g. of greensolid had not dissolved in the acetonitrile. The 5.15 g. portion ofgreen solid was recrystallized from ethyl acetate (350 ml.) and dried at90° C. in a vacuum oven for twenty hours to yield, as pale green prisms,4.01 g. of 3-ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. 244°-246° C. Also the original 2.56g. of insoluble green solid was recrystallized from ethyl acetate (150ml.) and dried at 90° C. in vacuo to yield another 1.5 g. of product.The 4.01 g. and 1.51 g. portions of product were combined and dried in avacuum oven at 100° C. for over sixty hours to yield 5.38 g. of saidproduct, m.p. 244°-246° C.

G-4.1,3-Dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 9.04 g. of3-amino-2-(2-hydroxyethylamino)-5-(4-pyridinyl)pyridine, 14.61 g. ofurea and 300 ml. of dimethylformamide was refluxed with stirring forover twenty hours and the dimethylformamide was distilled off in vacuo.The resulting residue was suspended in water and the solid wascollected, recrystallized from isopropyl alcohol (final volume 600 ml.),and dried at 90° C. in a vacuum oven for over sixteen hours to yield7.84 g. of product and a second portion of 2.18 g. after concentratingthe filtrate to a volume of 100 ml. The combined 7.84 g. and 2.18 g.portions of the product were combined and recrystallized from methanol(final volume of 250 ml.) and dried in a vacuum oven at 90° C. for oversixteen hours to yield 6.54 g. of product. A 6.50 g. portion of thisproduct was mixed with 200 ml. of an equimolar mixture of diphenyl anddiphenyl ether and the mixture was stirred under reflux for ninetyminutes and partially cooled. The resulting suspension was diluted withn-hexane and the tan solid was collected and combined with another 0.95g. portion of the product prepared in another run by the same procedureand the combined solids were recrystallized from methanol (final volumeof 100 ml.) and dried at 90° C. in a vacuum oven for over sixty hours toyield, as light-brown prisms, 4.26 g. of1,3-dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one,m.p. 283°-284° C. The product was then dissolved in 150 ml. ofdimethylformamide and the solution was treated with a slight excess ofhydrogen chloride in ethanol, the mixture was diluted with ether, andthe resulting solid was collected, dried in a vacuum oven at 85° C. forover sixty hours to yield, as a tan solid, 4.44 g. of1,3-dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-onemonohydrochloride hemihydrate, m.p. 297°-299° C. with decomposition.

G-5.1,3-Dihydro-3-(2-dimethylaminoethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 6.67 g. of3-amino-2-(2-dimethylaminoethylamino)-5-(4-pyridinyl)pyridine, 6.30 g.of carbonyldiimidazole and 150 ml. of dimethylformamide was stirred in awater bath at 35°-40° C. for over two hours and then at 70°-75° C. forover two hours. To the reaction mixture was added 10 ml. of water andthe solvents were distilled off in vacuo. The residual brown oil wascrystallized from acetonitrile (final volume of 50 ml.) and dried in avacuum oven at 83° C. for sixteen hours to yield 6.41 g. of product.This product was recrystallized a second time from acetonitrile (finalvolume of 125 ml.) and dried as above to yield 5.72 g. of white solid1,3-dihydro-3-(2-dimethylaminoethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one,m.p. 182°-184° C.

G-6.1,3-Dihydro-3-(3-dimethylaminopropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one,m.p. 188°-191° C., 7.53 g., was obtained following the proceduredescribed in Example G-5 using 14.72 g. of3-amino-2-(3-dimethylaminopropylamino)-5-(4-pyridinyl)pyridine, 13.13 g.of carbonyldiimidazole and 300 ml. of dimethylformamide.

G-7.1,3-Dihydro-3-[2-(4-morpholinyl)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 15.11 g. of3-amino-2-[2-(4-morpholinyl)ethylamino]-5-(4-pyridinyl)pyridine, 12.28g. of carbonyldiimidazole and 300 ml. of dimethylformamide was stirredat 35° C. for over one hour and then stirred at room temperature forsixteen hours. The resulting suspension was stirred with heating at 75°C. for over seventy-five minutes. To the cooled solution was addedanother 8.11 g. portion of carbonyldiimidazole and the resulting mixturewas stirred at about 35° C. for two and one-half hours, heated at about75° C. for forty-five minutes, and to the reaction mixture was added 15ml. of water. The water and dimethylformamide was distilled off in vacuoand the resulting oily material was washed with n-hexane whereuponcrystallization resulted. The crystalline material was thenrecrystallized from acetonitrile (160 ml.) and dried at 90° C. in avacuum oven for eighteen hours to yield 11.55 g. of1,3-dihydro-3-[2-(4-morpholinyl)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. 186°-190° C.

G-8. 1,3-Dihydro-1-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one

A mixture containing 4 g. of2-amino-3-methylamino-5-(4-pyridinyl)pyridine, 3.25 g. ofcarbonyldiimidazole and 100 ml. of dimethylformamide was stirred at roomtemperature for ninety minutes, with no apparent reaction taking place.The reaction mixture was then heated with stirring on a steam bath forfour hours and allowed to stand overnight at room temperature. Thesolvent was distilled off in vacuo and the residual solid was treatedwith water, collected by filtration, washed with water and dried. Thesolid was dissolved in 6 N hydrochloric acid and the excess aqueous aciddistilled off in vacuo. The remaining residue was recrystallized twicefrom methanol using decolorizing charcoal, washed successively withethanol and ether and dried in vacuo at 70° C. The resultinghydrochloride salt of the product was dissolved in water, the aqueoussolution made the weakly basic with 10% aqueous potassium bicarbonatesolution and the mixture cooled. The solid was collected, washed withwater and dried in vacuo at 70° C., recrystallized from 50%ethanolic-acetonitrile, and the mixture cooled overnight in ice. Thesolid was collected, washed with ether and dried in vacuo at 70° C. toyield 2 g. of1,3-dihydro-1-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one,m.p. 195°-198° C.

Following the procedure described in Example G-2 but using in place of3-amino-2-methylamino-5-(4-pyridinyl)pyridine a molar equivalentquantity of the appropriate 3-amino-2-R₃ NH-5-PY-6-Q-pyridine, it iscontemplated that the 1,3-dihydro-3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones of Example G-9 thru G-26 canbe obtained.

G-9.1,3-Dihydro-3-n-propyl-6-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-10.1,3-Dihydro-3-isopropyl-6-(2-methyl-5-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-11.3-n-Butyl-1,3-dihydro-6-(5-methyl-3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-12.3-n-Amyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-13.1,3-Dihydro-3-n-hexyl-6-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-14.1,3-Dihydro-5-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-15.1,3-Dihydro-5-n-propyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-16.1,3-Dihydro-5-isopropyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-17.1,3-Dihydro-5-n-butyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-18.1,3-Dihydro-5-isobutyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-19.1,3-Dihydro-6-(4-pyridinyl)-5-tert.-butyl-2H-imidazo[4,5-b]pyridin-2-one.

G-20.1,3-Dihydro-5-n-pentyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-21.1,3-Dihydro-3-(2-ethoxyethyl)-5-ethyl-6-(2-methyl-4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-22.5-Ethyl-1,3-dihydro-3-(2-methoxyethyl)-6-(3-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-23.1,3-Dihydro-3-(3-methoxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-24.1,3-Dihydro-3-(2-hydroxyethyl)-5-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-25.1,3-Dihydro-3-(3-hydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-26.1,3-Dihydro-3-(2,3-dihydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

Following the procedure described in Example G-8 but using in place of2-amino-3-methylamino-5-(4-pyridinyl)pyridine a molar equivalentquantity of the appropriate 2-amino-3-R₁ NH-5-PY-6-Q-pyridine, it iscontemplated that there can be obtained the corresponding1,3-dihydro-1-R₁ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones of ExamplesG-27 thru G-37.

G-27.1-Ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-28.1,3-Dihydro-1-n-propyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-29.1,3-Dihydro-1-isopropyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-30.1-n-Butyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-31.1,3-Dihydro-1-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-32.1,3-Dihydro-1-(2,3-dihydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-33.1,3-Dihydro-1-(3-methoxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-34.1,3-Dihydro-1-(2-ethoxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-35.1,3-Dihydro-1-(2-dimethylaminoethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-36.1,3-Dihydro-1-(3-diethylaminopropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

G-37.1,3-Dihydro-1-[2-(4-morpholinyl)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.

H. 1,3-DIHYDRO-1-R₁ -3-R₃ -6-PY-5-Q-2H-IMIDAZO[4,5-b]PYRIDINE-3-THIONES

H-1. 1,3-Dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione

To a mixture containing 18 g. of 2,3-diamino-5-(4-pyridinyl)pyridinedihydrochloride, 180 ml. of ethanol and 80 ml. of water was added 25 ml.of 2 N aqueous potassium hydroxide solution and to this mixture wasadded 18 g. of potassium ethyl xanthate. The resulting reaction mixturewas refluxed for five hours and cooled. The excess solvents weredistilled off in vacuo and the residue was dissolved in water. Theaqueous solution was neutralized with acetic acid and the resultingprecipitate was collected and dried in vacuo at 70° C. This material wascombined with another 1 g. portion obtained in another smaller run andthe combined material was dissolved in 6 N hydrochloric acid and theacidic solution was treated with methanol and the resulting mixturecooled. The solid that separated was collected, washed with methanol anddried in vacuo at 70° C. This solid was recrystallized twice from 50%aqueous methanol, the second time using decolorizing charcoal, washedsuccessively with methanol and ether and dried in vacuo at 70° C. toyield 7.5 g. of1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thionehydrochloride, m.p. >300° C.

H-2.1,3-Dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione

A mixture containing 10 g. of3-amino-2-methylamino-5-(4-pyridinyl)pyridine, 13 g. of potassium ethylxanthate, 100 ml. of ethanol and 50 ml. of water was refluxed for twelvehours and then allowed to stand overnight at room temperature. Another13 g. of potassium ethyl xanthate was added and refluxing was continuedfor an additional fourteen hours. The solvent and excess reactants weredistilled off in vacuo and the residue was dissolved in water and theaqueous solution was neutralized with acetic acid. The resulting solidwas collected, recrystallized twice from dimethylformamide, washedsuccessively with ethanol and ether and dried in vacuo at 70° C. Thepartially hydrated product was dissolved in 1 N aqueous potassiumhydroxide solution and the mixture filtered through diatomaceous earth.The filtrate was neutralized with acetic acid, the solid collected,washed with water and dried in a vacuum over at 80° C. over the weekend(three days) to yield 8.5 g. of1,3-dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thionehydrate (3:1), m.p. >300° C.

In the following run, the same compound was obtained as its hemihydrate:a mixture containing 58.2 g. of3-amino-2-methylamino-5-(4-pyridinyl)pyridine, 93.2 g. of potassiumethyl xanthate, 580 ml. of ethanol and 200 ml. of water was refluxedwith stirring overnight (about fifteen hours). An additional 90 g. ofpotassium ethyl xanthate was added and the reaction mixture was refluxedwith stirring for another fifteen hours, and then concentrated todryness. The residue was dissolved in water and the aqueous solution wasneutralized with acetic acid. The solid was collected, washed withwater, recrystallized twice from dimethylformamide, dried in a vacuumoven at 60° C. overnight to yield 50 g. of yellow powder. The yellowpowder was slurried with 400 ml. of water and the aqueous mixture wasmade basic with 35% aqueous sodium hydroxide solution. The resultingsolution was made acid with acetic acid, the precipitate was collected,washed with water and dried in a vacuum oven at 60° C. overnight toyield, as a pale yellow powder, 47 g. of1,3-dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thionehemihydrate, m.p. >300° C.

Following the procedure described in Example H-2 but using in place of3-amino-2-methylamino-5-(4-pyridinyl)pyridine a molar equivalentquantity of the corresponding 2-R₃ NH-3-R₁ NH-5-PY-6-Q-pyridine, it iscontemplated that there can be obtained the 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridine-3-thiones of Examples H-3 throughH-11.

H-3.1,3-Dihydro-1-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-4.1-Ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-5.3-Ethyl-1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-6.1,3-Dihydro-3-(2-hydroxyethyl)-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-7.1,3-Dihydro-1-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-8.1,3-Dihydro-3-(2,3-dihydroxypropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-9.1,3-Dihydro-3-(2-methoxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-10.1,3-Dihydro-3,5-dimethyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

H-11.1,3-Dihydro-3-(2-hydroxyethyl)-5-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione.

I. 1-PY-2-(DIMETHYLAMINO)ETHENYL LOWER-ALKYL KETONES

I-1. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl methyl ketone

A mixture containing 20 g. of (4-pyridinyl)methyl methyl ketone[alternatively named 1-(4-pyridinyl)-2-propanone] and 30 cc. ofhexamethylphosphoramide was diluted with 65 cc. of dimethylformamidedimethyl acetal and the resulting mixture was refluxed for thirtyminutes. TLC analysis showed a single sport, thereby indicatingcompletion of the reaction (in another run, the reaction appeared to becomplete after thirty minutes at room temperature. The reaction mixturewas evaporated under reduced pressure using a rotary evaporator and apressure of about 15 mm., thereby resulting in a crystalline residueweighing 24 g. The residue was decolorized using continuous columnchromatography on alumina (about 150 g.) using refluxing chloroform.After 1 and 1/2 hours, the extract was heated in vacuo to remove thechloroform, thereby leaving, as a light yellow crystalline material,23.2 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone,alternatively named 3-dimethylamino-4-(4-pyridinyl)-3-buten-2-one.

The above preparation can be carried out using in place ofhexamethylphosphoramide other solvents, e.g., dimethylformamide,acetonitrile or others noted above; however, hexamethylphosphoramide wasconveniently used since (4-pyridinyl)methyl methyl ketone wasconveniently prepared as a mixture together withhexamethylphosphoramide, as seen by the following preparation: To astirred solution containing 70 cc. of freshly distilled diisopropylamineand 200 cc. of tetrahydrofuran at 0° C. under nitrogen was addeddropwise over twenty minutes 210 cc. of 2.4 M n-butyllithium in n-hexaneand the reaction mixture was stirred for about thirty-five minutes atabout 0°-5° C. To the cold solution was added dropwise over a period often minutes 90 cc. of dry hexamethylphosphoramide (no temperaturechange) and a resulting light yellow solution was stirred for fifteenminutes. To the cold solution at 0° C. was added a solution of 50 cc. of4-picoline in 150 cc. of dry tetrahydrofuran over a fifteen minuteperiod and stirring was continued for thirty minutes at 0° C. Next, amixture containing 50 cc. of dry ethyl acetate and 150 cc. oftetrahydrofuran was added over a fifteen minutes period (temperaturerose from 0° to about 6° C.) and the resulting mixture was stirred fortwenty minutes at 0° C. The ice bath was then removed and stirringcontinued for another ninety minutes whereupon the temperature of thereaction mixture rose to about 25° C. The reaction mixture was thencooled in an ice bath and to it was added 60 cc. of acetic acid over aperiod of about thirty minutes. The tetrahydrofuran was distilled offusing a rotary evaporator in vacuo. The remaining mixture was dilutedwith 400 cc. of water and the aqueous mixture was extracted successivelywith two 250 cc. portions of isopropyl acetate and three 80 cc. portionsof chloroform. The solvents were distilled off under reduced pressure toyield about 137 g. of a mixture consisting primarily of the desiredproduct and hexamethylphosphoramide. Another run using the samequantities was carried out as above except after the addition of 60 cc.of glacial acetic acid, the mixture was diluted with only 200 cc. ofwater, the phases were separated, and the aqueous phase was extractedwith five 100 ml. portions of chloroform. The chloroform extract waswashed with saline solution and the chloroform was distilled off invacuo. The remaining mixture of the desired ketone andhexamethylphosphoramide was combined with the above 137 g. of the samemixture and the combined mixture was distilled under reduced pressure toyield the following fractions: I. 63 g. b.p. of 110°-112° C. at 4 mm.;II. 59 g. of pale yellow oil, b.p. 113°-115° C. at 3 mm.; and, III. 69g. of pale yellow oil, b.p. 115°-118° C. at 2.5 mm. Examination offraction III by NMR showed it to consist of a 2:3 mixture by weight of(4-pyridinyl)methyl methyl ketone and hexamethylphosphoramide.

Acid-addition salts of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methylketone are conveniently prepared by adding to a mixture of 5 g. of1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone in about 100 ml.of aqueous methanol the appropriate acid, e.g., methanesulfonic acid,concentrated sulfuric acid, concentrated phosphoric acid, to a pH ofabout 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitated salt, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each of 1-(4-pyridinyl)-2-(dimethylamino)ethenylmethyl ketone and the appropriate acid, e.g., lactic acid orhydrochloric acid, to prepare respectively and the monoactate ormonohydrochloride salt in aqueous solution.

I-2. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone

A mixture containing 87.5 g. of (4-pyridinyl)methyl ethyl ketone[alternatively named 1-(4-pyridinyl)-2-butanone] and 160 cc. ofhexamethylphosphoramide was diluted with 100 g. of dimethylformamidedimethyl acetal and the resulting mixture was stirred under nitrogen atroom temperature for forty-five minutes. The methanol formed by thereaction was distilled off in vacuo using a rotary evaporator and theremaining material was distilled under reduced pressure to yield twofractions, one boiling at 45°-80° C. at 0.5 mm. and the second at90°-95° C. at 0.5 mm. After TLC analysis showed predominantly only asingle spot for each fraction, the two fractions were combined (135 g.)and taken up in 600 cc. of chloroform. The resulting solution was washedwith two 300 cc. portions of water and the water was back extracted withthree 100 cc. portions of chloroform. The combined chloroform solutionwas dried over anhydrous sodium sulfate and decolorized by running itthrough 300 cc. of alumina in a 500 cc. continuous extraction columnfollowed by extraction with efluxing chloroform. The chloroform wasdistilled off in vacuo to yield a red oil which crystallized on standingovernight in an ice bath. The crystalline material was dissolved incarbon tetrachloride, cyclohexane was added and the mixture cooled toyield 64 g. of the resulting yellow crystalline product,1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone. Another 11 g. ofcrystalline product was obtained by passing the mother liquor throughthe continuous extraction column and using refluxing chloroform as thesolvent.

The above intermediate (4-pyridinyl)methyl ethyl ketone was obtained ina mixture with hexamethylphosphoramide as follows: To a mixturecontaining 200 cc. of tetrahydrofuran and 70 cc. of diisopropylamineunder nitrogen at 0°-5° C. was added 210 cc. of 2.4 n-butyllithium inn-hexane and the resulting mixture was stirred for thirty minutes. Nextwas added over a ten minute period 90 cc. of hexamethylphosphoramidefollowed by stirring of the mixture for fifteen minutes. Then was addedover a fifteen minute period a solution of 48 cc. of 4-picoline in 150cc. of tetrahydrofuran followed by stirring for thirty minutes at about0° C. The ice/acetone bath cooling the reaction mixture was replacedwith a dry ice/acetone bath and to the reaction mixture was added over atwenty minute period a mixture of 75 cc. of ethyl propionate in an equalvolume of tetrahydrofuran. The reaction mixture was then allowed to warmup to room temperature over a period of about ninety minutes and thenwas warmed at about 35° C. for thirty minutes. The mixture was nextcooled in an ice/acetone bath and to it was added 60 cc. of glacialacetic acid over thirty minutes. The resulting pale yellow suspensionwas diluted with 200 cc. of water. The mixture was extracted with three150 cc. portions of ethyl acetate and the ethyl acetate extract was backwashed with saline solution. The extract was heated in vacuo to removethe ethyl acetate and the residue was taken up again with ethyl acetate.The solution was washed with water and then heated in vacuo to removethe ethyl acetate followed by heating the residue in vacuo at 50° C. forabout thirty minutes to yield 100 g. of pale yellow oil. The pale yellowoil was combined with corresponding samples obtained from two additionalruns and then distilled in vacuo to yield a 256 g. fraction, b.p.85°-105°0 C. at 0.5-1.0 mm. The NMR of this fraction showed it to be amixture of (4-pyridinyl)methyl ethyl ketone and hexamethylphosphoramidein a respective molar ratio of 1:1.55, that is, 35% or 0.35×256=90 g. ofsaid ketone.

Following the procedure described in Example I-2 but using a molarequivalent quantity of the appropriate PY-methyl lower-alkyl ketone (II)in place of (4-pyridinyl)methyl ethyl ketone, it is contemplated thatthe corresponding 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketones ofExamples I-3 thru I-17 can be obtained.

I-3. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl methyl ketone using(3-pyridinyl)methyl methyl ketone.

I-4. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone using(4-pyridinyl)methyl n-propyl ketone.

I-5. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl isopropyl ketone using(4-pyridinyl)methyl n-butyl ketone.

I-6. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-butyl ketone using(4-pyridinyl)methyl n-butyl ketone.

I-7. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl isobutyl ketone using(4-pyridinyl)methyl isobutyl ketone.

I-8. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl tert.-butyl ketone using(4-pyridinyl)methyl tert.-butyl ketone.

I-9. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-pentyl ketone using(4-pyridinyl)methyl n-pentyl ketone.

I-10. 1-(2-Methyl-4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketoneusing (2-methyl-4-pyridinyl)methyl ethyl ketone.

I11. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone using(3-pyridinyl)methyl ethyl ketone.

J. 1,2-DIHYDRO-6-(LOWER-ALKYL)-2-OXO-5-PY-NICOTINONITRILES

J-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile,alternatively named1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridin]-5-carbonitrile

To a mixture containing 23 g. of1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. ofα-cyanoacetamide dissolved in 400 cc. of dimethylformamide was addedwith stirring 14 g. of sodium methoxide and the resulting reactionmixture was heated in an oil bath under gentle reflux for one hour. TLCanalysis showed no starting material in the reaction mixture which wasthen concentrated in vacuo on a rotary evaporator to a volume of about80 cc. The concentrate was treated with about 160 cc. of acetonitrileand the resulting mixture was stirred on a rotary evaporator withwarming until homogeneous and then cooled. The crystalline product wascollected, rinsed successively with acetonitrile and ether, and driedovernight at 55° C. to yield 28 g. of tan crystalline product, namely,sodium salt of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presenceof cyano being confirmed by IR analysis. An 8 g. portion of said sodiumsalt was dissolved in 75 cc. of hot water, the aqueous solution treatedwith decolorizing charcoal filtered, the filtrate again treated withdecolorizing charcoal and filtered, and the filtrate acidified with 6 Nhydrochloric acid by dropwise addition to a pH of 3. The acidic mixturewas diluted with ethanol and cooled. The crystalline product wascollected, dried, recrystallized from dimethylformamide-water and driedto produce 3.75 g. of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300° C.

Acid-addition salts of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile areconveniently prepared by adding to a mixture of 2 g. of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile areconveniently prepared by adding to a mixture of 2 g. of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40ml. of aqueous methanol the appropriate acid, e.g., methanesulfonicacid, concentrated sulfuric acid, concentrated phosphoric acid, to asmall pH of about 2 to 3, chilling the mixture after partial evaporationand collecting the precipitated salt, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile and theappropriate acid, e.g., lactic acid or hydrochloric acid, to preparerespectively the monolactate or monohydrochloride salt in aqueoussolution.

J-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile,alternatively named2-ethyl-1,6-dihydro-6-oxo-[3,4'-bipyridin]-5-carbonitrile, m.p. >300°C., 11.6 g., was prepared following the procedure described above inExample J-1 using 20 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenylethyl ketone, 8.4 g. of α-cyanoacetamide, 16.2 g. of sodium methoxideand 250 cc. of dimethylacetamide (as solvent in place ofdimethylformamide).

Following the procedure described in Example D-2 but using a molarequivalent quantity of the appropriate 1-PY-2-(dimethylamino)ethenyllower-alkyl ketone in place of 1-(4-pyridinyl)-2-(dimethylamino)ethenylethyl ketone, it is contemplated that the corresponding1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles of Examples J-3 thru J-17can be obtained.

J-3. 1,2-Dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinonitrile, using1-(3-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone.

J-4. 1,2-Dihydro-2-oxo-6-n-propyl-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone.

J-5. 1,2-Dihydro-6-isopropyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl isopropyl ketone.

J-6. 6-n-Butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-butyl ketone.

J-7. 1,2-Dihydro-6-isobutyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-dimethylamino)ethenyl isobutyl ketone.

J-8. 1,2-Dihydro-2-oxo-5-(4-pyridinyl-6-tert.-butyl-nicotinonitrile,using 1-(4-pyridinyl)-2-(dimethylamino)ethenyl tert.-butyl ketone.

J-9. 1,2-Dihydro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-pentyl ketone.

J-10. 6-Ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinonitrile,using 1-(2-methyl-4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone.

J-11. 6-Ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile, using1-(3-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone.

K. 1,2-DIHYDRO-6-(LOWER-ALKYL)-2-OXO-5-PY-NICOTINIC ACIDS

Following the procedure described in Example B-1 of U.S. Pat. No.4,072,746 but using in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile a molar equivalentquantity of the corresponding1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)nicotinonitrile, it iscontemplated that there can be obtained the1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)nicotonic acids of Examples K-1through K-11.

K-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid.

K-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid.

K-3. 1,2-Dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinic acid.

K-4. 1,2-Dihydro-2-oxo-6-n-propyl-5-(4-pyridinyl)nicotinic acid.

K-5. 1,2-Dihydro-2-oxo-6-isopropyl-5-(4-pyridinyl)nicotinic acid.

K-6. 6-n-Butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid.

K-7. 1,2-Dihydro-6-isobutyl-2-oxo-5-(4-pyridinyl)nicotinic acid.

K-8. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)-6-tert.-butylnicotinic acid.

K-9. 1,2-Dihydro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinic acid.

K-10. 6-Ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinic acid.

K-11. 6-Ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid.

L. 6-(LOWER-ALKYL)-3-NITRO-5-PY-2(1H)-PYRIDINONES

Following the procedure described in Example C-1 of U.S. Pat. No.4,072,746 but using in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid a molar equivalentquantity of the corresponding1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)-nicotinic acid, it iscontemplated that there can be obtained the3-nitro-5-PY-6-(lower-alkyl)-2(1H)pyridinones of Examples L-1 throughL-11.

L-1. 6-Methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

L-2. 6-Ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

L-3. 6-Methyl-3-nitro-5-(3-pyridinyl)-2(1H)pyridinone.

L-4. 3-Nitro-6-n-propyl-5-(4-pyridinyl)-2(1H)pyridinone.

L-5. 3-Nitro-6-isopropyl-5-(4-pyridinyl)-2(1H)pyridinone.

L-6. 6-n-Butyl-3-nitro-5-(4-pyridinyl)-2(1H)pyridinone.

L-7. 6-Isobutyl-3-nitro-5-(4-pyridinyl)-2(1H)pyridinone.

L-8. 3-Nitro-5-(4-pyridinyl)-6-tert.-butyl-2(1H)pyridinone.

L-9. 3-Nitro-6-n-pentyl-5-(4-pyridinyl)-2(1H)pyridinone.

L-10. 6-Ethyl-5-nitro-5-(2-methyl-4-pyridinyl)-2(1H)-pyridinone.

L-11. 6-Ethyl-3-nitro-5-(3-pyridinyl)-2(1H)-pyridinone.

M. 6-(LOWER-ALKYL)-5-PY-2(1H)-PYRIDINONES

Following the alternative procedure described in Example C-1 from line59 of column 15 to line 2 of column 16 of U.S. Pat. No. 4,072,746 butusing in place of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile amolar equivalent quantity of the corresponding1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)-nicotinonitrile, it iscontemplated that there can be obtained the5-PY-6-(lower-alkyl)-2(1H)-pyridinones of Examples M-1 through M-11.

M-1. 6-Methyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-2. 6-Ethyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-3. 6-Methyl-5-(3-pyridinyl)-2(1H)-pyridinone.

M-4. 6-n-Propyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-5. 6-Isopropyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-6. 6-n-Butyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-7. 6-Isobutyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-8. 5-(4-Pyridinyl)-6-tert.-butyl-2-(1H)-pyridinone.

M-9. 6-n-Pentyl-5-(4-pyridinyl)-2(1H)-pyridinone.

M-10. 6-Ethyl-5-(2-methyl-4-pyridinyl)-2(1H)pyridinone.

M-11. 6-Ethyl-5-(3-pyridinyl)-2(1H)-pyridinone.

The usefulness of the compounds of formula I or salts thereof ascardiotonic agents is demonstrated by their effectiveness in standardpharmacological test procedures, for example, in causing a significantincrease in contractile force of the isolated cat atria and papillarymuscle and/or in causing a significant increase in the cardiaccontractile force in the anesthetized dog with low or minimal changes inheart rate and blood pressure. Detailed descriptions of these testprocedures appear in U.S. Pat. No. 4,072,746, issued Feb. 7, 1980.

When tested by said isolated cat atria and papillary muscle procedure,the compounds of formula I or pharmaceutically-acceptable acid-additionsalts thereof at doses of 1, 3, 10, 30, 100 and/or 300 μg./ml., werefound to cause significant increases, that is, greater than 25% inpapillary muscle force and significant increases, that is, greater than25%, in right atrial force, while causing a lower percentage increase(about one-third or less than the percentage increase in right atrialforce or papillary muscle force) in right atrial rate. For example, whentested at said dose levels by this procedure, the following preferredcompounds were found to cause increases of 70% and greater in papillarymuscle force and/or right atrial force: the compounds of Examples G-1,G-2, G-3, G-4, G-5, G-7, G-8, H-1 and H-2.

When tested by said anesthetized dog procedure, the compounds of formulaI or pharmaceutically-acceptable acid-addition salts thereof at doses of0.1, 0.3, 1.0, 3.0 and/or 10 mg./kg. administered intravenously werefound to cause significant increases, that is, 25% or greater, incardiac contractible force or cardiac contractility with lower changesin heart rate and blood pressure. For example, when tested at said doselevels by this procedure, the following preferred compounds were foundto cause increases of 70% and greater in contractile force and lowerchanges in heart rate and blood pressure: the compounds of Examples G-1,G-2, G-3, G-4, G-5, H-1 and H-2. When tested orally in theunanesthetized dog at 1.0, 3.0 and 10.0 mg./kg., the compound of ExampleG-4 was found to cause cardiac contractile force increases of 30, 54 and104%, respectively, while causing respective heart rate increases of 9,19 and 31%, and respective diastolic blood pressure changes of +4%, -6%and -1%.

When screened by other standard pharmacological test procedures, someembodiments of the compounds of formula I or salts were found to haveantihypertensive and/or bronchodilator activities. For example, thecompounds of Examples G-1 and G-2 were found to have oral AHD₄₀ valuesof 40 and 30 mg./kg. when tested in the spontaneously hypertensive rat;similarly, the compounds of Examples G-4 and G-5 were found to have lowantihypertensive activities (AHD₄₀ values of 50 mg./kg. p.o.) whentested by this procedure. When tested orally at 100 mg./kg., thecompounds of Examples G-1, G-2 and G-3 were each found to havebronchodilator activity by inhibiting bronchoconstriction induced byhistamine, acetylcholine or immune complex in guinea pigs.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, the cardiotonic compound of formula I orpharmaceutically-acceptable acid-addition salt thereof. The inventionalso includes within its scope the method for increasing cardiaccontractility in a patient requiring such treatment which comprisesadministering to such patient an effective amount of cardiotoniccompound of formula I or pharmaceutically-acceptable acid-addition saltthereof. In clinical practice said compound or salt thereof willnormally be administered orally or parenterally in a wide variety ofdosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions canalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater and liquid paraffin. Besides inert diluents such compositions canalso contain adjuvants, such as wetting and suspending agents, andsweetening, flavoring perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilising, preserving,wetting, emulsifying and dispersing agents.

They can be sterilized, for example, by filtration through abacteria-retaining filter, by incorporation of sterilising agents in thecompositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentages of active component in the said composition and methodfor increasing cardiac contractility can be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing the best judgement on the patient's behalf.

We claim:
 1. A 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thione having the formula##STR5## where Z is O or S, Q is hydrogen or lower-alkyl, R₁ and R₃ eachare hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl,lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least twocarbon atoms between its connecting linkages and NB isdi-(lower-alkyl)amino or 4-morpholinyl, at least one of R₁ or R₃ beinghydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one ortwo lower-alkyl substituents, or pharmaceutically-acceptableacid-addition salt thereof.
 2. A compound according to claim 1 where PYis 4-pyridinyl or 3-pyridinyl.
 3. A compound according to claim 1 whereQ is hydrogen, methyl or ethyl.
 4. A compound according to claim 1 whereZ is O.
 5. A compound according to claim 1 where R₃ is hydrogen when R₁is methyl, ethyl or 2-hydroxyethyl.
 6. A compound according to claim 1where R₁ is hydrogen when R₃ is methyl, ethyl or 2-hydroxyethyl.
 7. Acompound according to claim 1 where R₁ is hydrogen, R₃ is2-hydroxyethyl, PY is 4-pyridinyl and Q is hydrogen, methyl or ethyl. 8.1,3-Dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-oneor pharmaceutically-acceptable acid-addition salt thereof.
 9. Acardiotonic composition for increasing cardiac contractility, saidcomposition comprising a pharmaceutically-acceptable inert carrier and,as the active component thereof, an effective amount of a cardiotonic1,3-dihydro-1-R₁ -3-R₃ -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or-2-thione or pharmaceutically-acceptable acid-addition salt thereof,where Z is O or S, Q is hydrogen or lower-alkyl, R₁ and R₃ each arehydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl,lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least twocarbon atoms between its connecting linkages and NB isdi-(lower-alkyl)amino or 4-morpholinyl, at least one of R₁ or R₃ beinghydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one ortwo lower-alkyl substituents.
 10. A composition according to claim 9where the active component is1,3-dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-oneor pharmaceutically-acceptable acid-addition salt thereof.
 11. Themethod for increasing cardiac contractility in a patient requiring suchtreatment which comprises administering orally or parenterally in asolid or liquid dosage form to such patient an effective amount of thecardiotonic 1,3-dihydro-1-R₁ -3-R₃-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-one or -2-thione orpharmaceutically-acceptable acid-addition salt thereof, where Z is O orS, Q is hydrogen or lower-alkyl, R₁ and R₃ each are hydrogen,lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkylor Y-NB where Y is lower-alkylene having at least two carbon atomsbetween its connecting linkages and NB is di-(lower-alkyl)amino or4-morpholinyl, at least one of R₁ or R₃ being hydrogen, and PY or 4- or3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkylsubstituents.
 12. The method according to claim 11 where the cardiotonicis1,3-dihydro-3-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-oneor pharmaceutically-acceptable acid-addition salt thereof.